This project involves clinical investigation of strategies to improve results of chemotherapy and biologic treatment of CML. Aim 1 builds upon the success of the program in defining the activity of interferon-alpha for CML and more recently the combination of interferon and cytarabine. We will test the hypothesis that the combination of interferon-alpha, cytarabine and ATRA improves outcome compared to interferon- alpha/cytarabine treatment. Aim 2 is directed to evaluation of a decitabine, a novel chemotherapeutic agent with a unique mechanism of action to determine if it an induce significant and durable suppression of the Ph-positive cells in late chronic phase CML and/or in interferon alpha (IFN-A) resistant CML disease. The effects of this agent on DNA methylation will be studied and related to the evaluation of epigenetic alterations in Project 9. Aims 3 and 4 are directed to evaluating novel biologic agents in patients failing to have a major response to interferon. Aim 3 develops therapeutic approaches to overcome resistance to interferon-alpha via the inhibition of cellular production of interleukin 1-beta evaluation of interleukin-1 receptor antagonist. In aim 4, the objective is to identify biologics which improve cytogenetic response to interferon. In a pilot study, the combination of interferon- alpha and GM-CSF has produced marked cytogenetic responses in interferon resistant patients; this combination will be studied in a larger phase II trial to evaluate its potential efficacy. This project interacts extensively with he basic science projects within this proposal, particularly, Project 5 (Molecular Sensitization of p210 Bcr-Abl Positive Cells to Therapy), Project 4 (Stem Cell Prognosticators of Sensitivity & Resistance in CML) and Project 9(Epigenetic Alterations in CML).